BridgeBio Stands Up to Pfizer in ATTR-CM with Late-Stage Data

BridgeBio's Attruby Shows Survival, Hospitalization Benefits in ATTR-CM

BridgeBio’s transthyretin amyloidosis drug Attruby elicited notable improvements in survival and hospitalization rates, pointing to its potential “superiority” over competing products from Pfizer, analysts say. In the Phase 3 ATTRibute-CM study, BridgeBio enrolled more than 630 patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM), who were randomly assigned to receive either Attruby or placebo. An additional analysis of the trial, conducted by the Mater Misericordiae University Hospital in Ireland, employed anchored matching to indirectly compare Attruby to Pfizer’s tafamidis, marketed as Vyndaqel or Vyndamax. Results of this matched analysis, disclosed Monday, showed that patients on Attruby had a 34% decrease in cardiovascular hospitalization versus tafamidis—an effect that was statistically significant. Attruby also lowered the risk of all-cause mortality (ACM) by 28% versus Pfizer’s product, though this benefit fell short of significance. These findings provide “a glimpse of Attruby’s [potential] superiority in ATTR-CM,” analysts at Jefferies told investors in a note on Monday afternoon, “although cross-trial comparisons are a key caveat.” Jefferies is expecting more than $3 billion in peak sales for Attruby.

• The matched analysis of the ATTRibute-CM study revealed that Attruby led to a statistically significant 34% reduction in cardiovascular hospitalization compared to Pfizer’s tafamidis. Additionally, Attruby showed a 28% lower risk of all-cause mortality, although this benefit did not reach statistical significance. These findings, while subject to cross-trial comparison caveats, suggest potential superiority.
• BridgeBio also presented biomarker data for Attruby, demonstrating a significant increase in serum transthyretin and minimized variability in its levels. These dynamics are associated with all-cause mortality risk. Attruby is an orally administered transthyretin stabilizer that binds to the protein, slowing its breakdown and preventing plaque formation in ATTR-CM patients.
• Attruby was approved in November 2024, five years after the tafamidis franchise (approved 2019). Pfizer's tafamidis products generated nearly $1.7 billion in revenue last year, while Attruby clocked $362.4 million. Pfizer recently secured patent extensions through June 1, 2031, for its tafamidis line via settlement agreements with generics manufacturers, potentially worth up to $6 billion.

ATTRibute-CM: Unpacking Attruby's Latest Efficacy and Safety Data

The ATTRibute-CM trial represents a landmark phase 3 study evaluating acoramidis, an oral transthyretin stabilizer achieving near-complete (≥90%) TTR stabilization. This randomized, placebo-controlled study enrolled 632 participants with ATTR-CM in a 2:1 ratio (acoramidis n=409; placebo n=202) and demonstrated remarkable efficacy outcomes. Acoramidis significantly reduced the composite of all-cause mortality or first cardiovascular-related hospitalization, with benefits observed as early as month 3. The treatment achieved a 49% reduction in cumulative risk of CV-related mortality or recurrent cardiovascular hospitalization through month 30 (HR: 0.51; 95% CI: 0.43-0.62; P<0.0001), translating to 53 events avoided per 100 treated participants. Additional benefits included improved 6-minute walk distances, stabilized myocardial thickness, improved NT-proBNP levels, and enhanced Kansas City Cardiomyopathy Questionnaire scores. The safety profile was robust throughout the clinical trial program, leading to FDA approval in 2024.

The foundational ATTR-ACT trial established tafamidis as the first disease-modifying therapy for ATTR-CM, with subsequent real-world evidence consistently validating its clinical benefits. Observational studies demonstrate that tafamidis treatment is associated with improved survival, reduced heart failure hospitalizations, and stabilization of cardiac biomarkers including NT-proBNP and troponin-T levels at one-year follow-up. Real-world patients typically present older and with more advanced disease compared to clinical trial populations, yet meaningful preservation of physical function is observed, particularly when therapy is initiated early in the disease course.

A comprehensive systematic review and meta-analysis published in February 2025 analyzed 17 studies encompassing 5,209 participants and reinforced the mortality benefits of transthyretin stabilizers. The analysis demonstrated significant reduction in all-cause mortality (OR 0.20; 95% CI 0.11-0.37; p<0.01), with the tafamidis subgroup maintaining significance (OR 0.25; 95% CI 0.13-0.48; p<0.01). Beyond survival benefits, treatment improved quality of life measures and functional capacity via 6-minute walk testing. The safety analysis revealed fewer adverse events (OR 0.19) and serious events (OR 0.54) compared to controls, establishing a favorable benefit-risk profile for this therapeutic class.

Attruby's Position in the Evolving ATTR-CM Treatment Landscape

The current treatment paradigm for ATTR-CM has fundamentally transformed since 2019, when tafamidis became the first FDA-approved disease-modifying therapy for this condition. Three distinct therapeutic categories now exist: transthyretin stabilizers (tafamidis and acoramidis), transthyretin silencers (vutrisiran), and gene silencing therapies (patisiran and inotersen). These targeted interventions act at different points of the amyloidogenic cascade and have converted ATTR-CM from an incurable disease to one with multiple therapeutic options. Additionally, broadly effective heart failure therapies, including mineralocorticoid receptor antagonists and sodium glucose-cotransporter 2 inhibitors, have demonstrated benefit in ATTR-CM patients as standard supportive care.

Clinical trial evidence demonstrates robust efficacy and adherence for current therapies, particularly tafamidis, which showed 97.2% patient adherence in the pivotal phase 3 ATTR-ACT trial. Real-world Medicare data from 2019-2021 confirmed high adherence rates across 3,558 patients, with mean medication possession ratios exceeding 90% and proportion of days covered rates of 79% or higher across all age groups. Tafamidis free acid formulation showed significantly superior adherence compared to tafamidis meglumine, likely due to enhanced convenience of once-daily single capsule dosing. Treatment outcomes are optimized when initiated earlier in the disease course, with patients having milder symptoms demonstrating greater therapeutic benefit and functional preservation.

Contemporary clinical trial design reflects this evolving treatment landscape, as patient populations in recent studies (APOLLO-B, ATTRibute-CM, HELIOS-B) represent earlier-stage disease compared to the original ATTR-ACT cohort. This shift toward earlier diagnosis and treatment initiation has resulted in healthier study populations with slower disease progression, though effect sizes between active treatment and placebo arms are consequently smaller than historically observed. Canadian real-world data from 139 ATTR-CM patients demonstrated that while 55% received tafamidis therapy, baseline risk factors including age, frailty, renal function, and right ventricular parameters remained independent predictors of mortality regardless of tafamidis treatment status.

Addressing Unmet Needs in Transthyretin Amyloidosis Cardiomyopathy

Current treatment approaches for transthyretin amyloidosis cardiomyopathy face significant limitations that highlight critical unmet medical needs. While FDA-approved therapies like tafamidis and acoramidis can stabilize the transthyretin protein and slow disease progression, they cannot reverse existing amyloid deposits that have already accumulated in cardiac tissue. These therapeutic gaps underscore the need for more comprehensive treatment strategies that address both disease prevention and reversal of established pathology.

• Limited efficacy of current stabilizers: FDA-approved transthyretin stabilizers (tafamidis and acoramidis) prevent protein breakdown into fibril-forming monomers but only halt disease progression without reversing existing amyloid deposits in cardiac tissue

• Diagnostic challenges impeding timely intervention: The disease frequently goes undiagnosed as it mimics hypertensive, hypertrophic heart disease, requiring increased clinical awareness of prevalence, signs, symptoms, and available diagnostic tools for proper discrimination

• Stage-dependent treatment effectiveness: Current therapies demonstrate greater efficacy in early disease stages, making prompt diagnosis crucial for optimal patient outcomes and limiting treatment options for advanced cases

• Insufficient mortality benefits from silencing agents: TTR silencers failed to significantly reduce mortality (RR: 0.79; 95% CI 0.37-1.68; p=0.54) or hospitalizations (RR: 1.11; 95% CI 0.83-1.48; p=0.48) compared with placebo, potentially due to shorter follow-up periods in clinical studies

• Limited combination therapy outcomes: Combination treatment with SGLT2-inhibitors and tafamidis showed no significant mortality reduction at 1-year or 3-year follow-up, though it reduced hospitalization and acute myocardial infarction rates

• Unmet need for amyloid removal: Accelerating the removal of existing amyloid deposits to complement current stabilization therapies remains a critical therapeutic goal, driving development of anti-amyloid treatments like ALXN2220 that stimulate macrophage-mediated phagocytosis

Attruby's Challenge: Reshaping ATTR-CM Treatment

The landscape for transthyretin amyloidosis cardiomyopathy (ATTR-CM) treatment has been significantly shaped by tafamidis, the first FDA-approved therapy that has demonstrated clear benefits in reducing mortality and cardiovascular hospitalizations, alongside improvements in quality of life. However, the substantial annual cost of tafamidis has consistently raised questions about its cost-effectiveness and broad patient access, creating an environment ripe for competition.

BridgeBio's recent disclosure regarding Attruby's Phase 3 ATTRibute-CM study, particularly the indirect comparison against tafamidis, introduces a compelling new dynamic. The analysis suggests Attruby could offer a 34% reduction in cardiovascular hospitalization compared to tafamidis, a statistically significant finding. While a 28% decrease in all-cause mortality was also observed, it did not reach statistical significance in this specific comparison. These results, if substantiated, could position Attruby as a potent challenger, potentially offering a new benchmark for efficacy in a disease where every improvement in patient outcomes is critical.

However, the strategic implications are nuanced. The "cross-trial comparison" caveat is paramount; such analyses are inherently limited and may not fully account for differences between study populations or designs. This means the perceived superiority, while exciting, requires further validation. BridgeBio will likely face pressure to conduct direct comparative trials or generate more robust real-world evidence to solidify Attruby's position. Success in this endeavor could enable BridgeBio to capture significant market share and potentially influence future pricing and access discussions, especially given the high cost of existing therapies. Conversely, the lack of statistical significance for mortality in this indirect comparison, coupled with tafamidis's extensive long-term data, represents a risk that could temper physician adoption and payer acceptance. The evolving ATTR-CM pipeline, including other TTR stabilizers and RNA interference therapies, further underscores the need for definitive evidence to differentiate new entrants and truly reshape patient care.